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Eugene Delay Laboratory Research

In recent years there has been a surge of interest in identifying membrane receptors responsible for detecting the taste of foods and other ingestible substances. Knowledge about these receptors may be very important for dietary regulation of people in general and may be especially important for people with health issues that lead to dietary challenges, e.g., diabetics, cardiovascular disease, elderly, mentally challenged. My research is focused on two areas of taste. One area of interest, supported by the National Science Foundation for the last four years, involves ongoing behavioral, physiological and molecular studies of taste transduction (receptor mechanisms), afferent signaling (CNS neuronal coding), and perception (behavioral) of umami and L-amino acid substances. These studies are summarized below. We also are developing research studies examining the effects of chemotherapy drugs on taste functions and on the morphological components of the peripheral portion of the system in the mouth and especially the tongue with the goal of determining whether detection of L-amino acids are adversely affected by chemotherapy drugs.

Umami and L-amino Acid Tastes

Umami is one of the five accepted basic tastes (umami, salt, sweet, sour, bitter) and is thought to signal the presence of protein in food. The prototypical umami substance is monosodium glutamate (MSG), an amino acid found in many common foods such as meats, vegetables, cheeses, and wines. Umami is defined by two characteristics. One is a unique taste sensation described as “savory” or “meaty”. The second defining characteristic is the ability of 5’- ribonucleotide monophosphates such as inositol monophosphate (IMP) and guanylate monophosphate to synergistically potentiate the intensity of umami. IMP and other monophosphates are often present in the same foods as MSG. Umami substances, especially MSG and IMP, are used in Japanese cuisine to increase the palatability of foods. Importantly, these compounds can also help improve the food intake of people who have dietary challenges. For example, people with hypertension find that a small amount of MSG is able to enhance the palatability of foods as much as a larger quantity of sodium chloride, thereby reducing their sodium intake. Others have found that a small amount of MSG can increase the amount of vegetables and other nutritionally desirable food items voluntarily eaten by mentally retarded patients, without increasing the total number of calories ingested. These findings strongly suggest that other populations such as the diabetics, the elderly who often need more seasoning to make foods more interesting and desirable, or those with food allergies may benefit from the taste enhancing properties of umami substances. Understanding how umami substances are able to enhance the taste of foods is of great interest to health care professions, nutritionists, and the food industry.

Our lab has been studying the mechanisms by which umami substances are detected and perceived for a number of years. Our early behavioral studies, in collaboration with other scientists 1-2, helped to identify a putative umami taste receptor, taste-mGluR4. Shortly after this receptor was found, others identified a second umami receptor, T1R1+T1R3, which some have argued is the only umami receptor of importance. Moreover, research findings have been reported showing that this receptor is a broadly tuned L-amino acid taste receptor. Data from our lab as well as others, however, suggest that multiple receptors may detect L-amino acids 3-4. Our current research is testing this hypothesis: L-amino acids are detected by multiple umami receptors. We have been testing this hypothesis using a combination of methodological approaches.

On-going behavioral studies are examining the similarities and differences in taste qualities of monosodium glutamate (MSG) and three other L-amino acids: L-alanine, L-serine and L-arginine. These amino acids were selected because they have quite different side chains. Mice are the animal model of choice because we also have mice strains that have been genetically modified to have the T1R3 (derived in Dr. Robert Margolskee’s lab) or the T1R1 (derived in Dr. Charles Zuker’s lab) receptor dimer deleted from their genome. These studies will provide new insights into whether one or more than one receptor type is activated by umami stimuli and which receptors are responsible for umami taste perception. These experiments are evaluating the perceptual capacity of these transgenic mice for a variety of taste stimuli and are helping us assess the potential contributions of each receptor to L-amino acid taste. We are also exploring other dimensions of glutamate taste perception as well. For example, one of the defining characteristics of umami taste is a synergistic interaction between 5' ribonucleotide monophosphates and umami substances, but curiously little is known about the taste qualities of these monophosphates. Several UVM undergraduates are working as a team to conduct these experiments. These students include David Viscido (team leader), Daniella Thorsdottir and Michael Gomella. (Daniella gets the prize for being the student in the lab who has travelled the farthest to be at UVM. Her home is in Iceland.)

A second approach to testing our hypothesis is calcium imaging of isolated taste sensory cells. If a taste sensory cell is responsive to a taste stimulus, then the cell will show an increase in intracellular calcium levels. Shreoshi Pal Choudhuri, a fourth year graduate student, has been testing these isolated taste cells with a battery of amino acids (MSG or MPG, L-arginine, L-serine, and L-glutamine), either presented alone or mixed with IMP. If a single receptor (T1R1+T1R3) is involved in detecting all L-amino acids, then the cell should respond similarly to all L-amino acids but if multiple receptors are able to detect these amino acid, then an isolated taste sensory cell might respond to only a subset of L-amino acids. Shreoshi has now tested several hundred cells and it appears that each isolated cell may exhibit a variety of potential response patterns, sometimes with the responses potentiated by the addition of IMP to the solution and sometimes IMP has no effect on the cells response to the amino acid. Interestingly, Shreoshi is finding that a high percentage of umami-responsive cells are able to detect IMP when presented alone. Shreoshi is now beginning a series of experiments to test the downstream signal pathways activated by these amino acids. These experiments are very exciting as they may provide some insight into how monophosphates synergistically enhance the taste of MSG and other L-amino acids. This work is in collaboration with Dr. Rona Delay, an expert in calcium imaging methods and the chemical senses.

We are also interested in whether the signals initiated by an amino acid are transmitted and processed by the same or different neurons in the nucleus of the solitary tract. I am combining immunocytochemical and in situ hybridization methods to "double-label" neurons in the brain stem that have responded to MSG and/or to another L-amino acid presented to the animal. After stimulation with a tastant, a responsive neuron will activate the c-fos gene and mRNA expression will increase (detected by in situ hybridication), peaking about 30 minutes later then declining. c-Fos protein then begins to increase, peaking about 90 minutes later (detected by immunocytochemistry). In this study we stimulate the mouse with two taste stimuli, separated by 90 minutes. If the taste signals for MSG and another L-amino acid are detected by the same receptors, then the signals would likely be carried to the brainstem by the same neurons (all would be double-labeled) but if there are multiple taste receptors involved, then these signals may be carried by different neurons to the brain stem and there would be many neurons with only one type of label. We are currently quantifying the results of these experiments. NSF initially helped fund this project. However, more recently funding for this work has been provided by Ajinomoto Inc. Diane Morgan has been working hard on this project. Emily Marshall (undergraduate) is working on a related project to determine if there is an increase in neural activity in the same structure of the brain stem if the mice have been given a chance to engage in wheel running (exercise) when they are maintained on an L-lysine free diet or a normal diet.

A fun project was added to the NSF funded research when we learned about dried-bonito dashi which is a stock solution used in Japanese cuisine, much like beef bouillon is used in American cuisine. Dashi is rich in ingredients that contribute to its taste and odor, but it is generally assumed that the taste of dashi is umami. We are interested in dashi both because of the presumed umami taste and because it has 17 different L-amino acids. We are using a behavioral method called conditioned taste aversion to determine if the taste of dashi is much more complex than primarily umami. A subset of L-amino acids mixed with IMP elicit taste sensations that are similar to dashi. Interestingly, the tastes of many of these amino acids are enhanced by lactic acid, a significant component of dashi. Mice missing the T1R1 receptor (T1R1 -/-) also experience a complex taste but they do not appear to sense the umami component of the taste sensations elicited by dashi. The results of these experiments are being prepared to publication.

We are now expanding the research on dashi to explore whether the minerals found in dashi also contribute to its complex taste sensation. Another team of UVM undergraduates are conducting these behavioral studies: Doug Lane (team leader), Tony Carbonar, Ben Weaver, and Kayo Nagai. We just received a one-year grant from the Ajinomoto Company to conduct these experiments.

Chemotherapy and Taste

Taste sensory cells, located in taste buds, are important for detecting substances that should be either ingested to provide metabolic compounds needed to maintain normal homeostasis or avoided because they are toxic. The location of taste buds in the mouth makes them susceptible to toxic or other tissue damaging agents from external or internal sources. Interestingly, the life span of taste sensory cells is relatively short, generally measured in days to a few weeks. This means that if the surface of the tongue is damaged (e.g., something too hot or is poisonous to taste cells), the normal process for sensory cell replacement can reestablish taste functions. How this process occurs is currently under study in our lab. Our initial work has been made possible by NSF funds because of its importance for our transduction research. We are very interested in how detection of L-amino acids might be affected by the loss of taste sensory cells. Our initial behavioral studies found that mice given a single moderate dose of cyclophosphamide elevates thresholds for MSG and IMP and reduces their ability to discriminate between higher concentrations of MSG and IMP. The drug also destroys taste buds, especially in the anterior portion of the tongue. The result is a reduced capacity to detect L-amino acids. We are intending to determine if mice with similar drug treatments will also lose their preferences for dashi and other basic tastes such as bitters. A team of Dave Harris (graduate student), Angela Brisson and Jack King (both undergraduates) are currently working on behavioral studies to examine the effects of cyclophosphamide on basic taste functions.